Oil suspension of metronidazole

ABSTRACT

The present invention relates to a palatable oral veterinary pharmaceutical composition consisting of an oil suspension of metronidazole and comprising metronidazole in an edible animal, vegetable or mineral oil and the use thereof for treating diarrhoea in animals, in particular giardiasis, or inflammatory diseases of the digestive tract.

The present invention relates to the development of a veterinarypharmaceutical composition based on metronidazole which exhibits a goodappetency for animals and to its use in the treatment of diarrhea inanimals, in particular giardiasis, or also inflammatory diseases of thedigestive tract.

Giardiasis (also known as lambliasis) is an intestinal infection causedby the parasite Giardia intestinalis or Giardia duodenalis (formallyGiardia lamblia), which is a flagellated protozoan. Giardia intestinalisnormally takes up residence in lakes, water courses or pondscontaminated by human and/or animal feces. The vegetative form (ortrophozoite) lives in the duodenum and measures 15 μm. The cyst formoccurs in the colon and measures approximately 10 μm; this is theinfecting form which lives in the colon and which occurs in the feces.This parasite is very resistant (it survives for 2 months at 8° C.); thenormal sterilization of drinking water is not sufficient to remove it;on the other hand, boiling and freezing destroy them.

Some studies describe a prevalence of 10% and 15% in cats and dogsrespectively. Infections are often asymptomatic but acute and persistentor intermittent chronic diarrhea of mucoid type may develop. This is adisease which is especially frequent in communities of cats, where thetransmission takes place directly. It is essentially the young animalswhich are affected.

Giardia diseases are routinely demonstrated by the direct examination offresh feces in a saline solution and after staining, for thedemonstration of trophozoites, or by sample concentration and thencentrifuging, for the demonstration of cysts. Diagnosis is not alwayseasy due to the intermittent excretion of the trophozoites and cysts.Various antigen tests are also marketed.

The recommended treatments are in particular:

-   -   the administration of fenbendazole at a dose of 50 mg/kg of body        weight per day for 5 days; this is the treatment most suitable        for kittens and puppies;    -   the administration of metronidazole at a dose of 25 mg/kg of        body weight twice daily for 5 days.

Furthermore, it is advisable to decontaminate the environment of theanimal using ammonia-based solutions and to bath the animal in order toremove the cysts which would be present on the fur.

Metronidazole is an antibiotic and an antiparasitic belonging to thenitroimidazoles.

Chemical Structure of Metronidazole

It inhibits the synthesis of nucleic acids and is used in the treatmentof infections related to anaerobic bacteria and also to protozoans. Itis effective against, inter alia: Giardia duodenalis, Entamoebahistolytica, Trichomonas vaginalis, bacteria of the Clostridium genus oralso Helicobacter pylori.

Metronidazole can be administered in the oral, intravenous or topicalform. In the oral form, it is absorbed and passes into the bloodstream,where it has a half-life of 6 to 8 hours.

Metronidazole is normally prescribed by veterinarians to treat diarrheain dogs, in particular giardiasis, and also chronic inflammatorydiseases of the intestines in cats.

Nevertheless, there does not currently exist a veterinary pharmaceuticalcomposition and the administration of metronidazole to animals takesplace with medicaments intended for man, usually in the form of tablets;this presents several problems:

-   -   the form of the human medicaments generally has to be modified        in order to render it compatible with the administration to an        animal (dissolution of a tablet, for example);    -   their dose does not correspond to that necessary for the animal        and thus has to be adjusted. In addition to being a constraint        for the carer of the animal, this “redosing” represent a risk of        error, indeed even of undesirable overdosing with metronidazole,        the commonest symptoms of which are vomiting, complete loss of        appetite, problems of coordination, fits of giddiness, and the        like;    -   finally, metronidazole is an extremely bitter active principle;        it is a product with a persistent metallic aftertaste which        results in lack of appetite and in aversion; it is consequently        difficult to make animals accept medicament comprising        metronidazole and to obtain sufficient observance.

It is in order to overcome these inconveniences that the applicantcompany has attempted to develop an oral veterinary pharmaceuticalcomposition comprising metronidazole which exists in the liquid form asthis is a pharmaceutical form which is economical to produce and veryeasy to dose. It has thus succeeded in preparing an oily metronidazolesuspension which, in addition to being stable and to exhibiting a formwhich facilitates the dosing and the oral administration to animals,proves to have an excellent appetency.

There are known, from the state of the art, specific pharmaceuticaldosage formulations for masking the taste of active principles whichrequire it; for example, the international application WO 2004/058137provides such a formulation in which 15% to 30% of active principle aremixed with 60% to 80% of a glycerol ester or of a fatty acid and of asurfactant; spray cooling of the mixture is subsequently carried out inorder to obtain solid particles with a particle size of less than 350μm.

However, while carrying out its studies on developing a liquidmedicament, the applicant company found that mixing of the activeprinciple with the glycerol ester or the fatty acid was not essential inorder for the medicament to be accepted by the animals and that an oilysuspension of metronidazole particles having a specific size was verywell accepted by animals despite the absence of coating of saidparticles. The fact of avoiding the coating presents obvious advantageswith respect to the state of the art, among which may be mentioned, forexample, a reduction in the number of ingredients and of stagesnecessary for the preparation of the coating, which results in asimplification in the manufacture and in a saving in terms of productioncosts.

The present invention thus relates to an oral veterinary pharmaceuticalcomposition consisting of an oily metronidazole suspension comprising:

-   -   between 5% and 30% by weight/volume of metronidazole; and    -   between 70% and 95% by weight/volume of at least one oily        vehicle;        characterized in that the metronidazole is provided in the form        of particles, 90% of which have an equivalent diameter strictly        greater than 6 μm; preferably, 90% of the metronidazole        particles have an equivalent diameter strictly greater than 6 μm        and less than or equal to 300 μm; more preferably, 90% of the        metronidazole particles have an equivalent diameter of strictly        between 50 and 250 μm; more preferably, 90% of the metronidazole        particles have an equivalent diameter of strictly between 90 and        250 μm, more preferably 90% of the metronidazole particles have        an equivalent diameter of strictly between 125 and 250 μm or        between 90 and 200 μm, and more preferably still 90% of the        metronidazole particles have an equivalent diameter of strictly        between 125 and 200 μm; the equivalent diameter is measured by        laser particle sizing, for example using a device of the Laser        Malvern Mastersizer 2000 type. These measurements make it        possible to obtain D50 (maximum size of at least 50% of the        particles) values and also D90 (maximum size of at least 90% of        the particles) values.

The expression “equivalent diameter” or “diameter” denotes, in thecontext of the present invention, the equivalent sphere diameter, thatis to say the mean diameter of the particle, which is regarded, byapproximation, as a perfect sphere. Alternatively, the particles arepassed through sieves, for example Retsch sieves, for example with adiameter of 20 cm. The sieving has the effect of only allowing particleswith a size of less than the value of the sieve to pass through themeshing: for example, a 180 μm sieve will make it possible to obtain acomposition, 100% of the particles of which have a particulate size ofless 180 μm in at least one of their dimensions. The value of themeshing of the sieve is comparable, in the context of the presentinvention, to a D90 value within the meaning of the laser particlesizing.

The applicant company has demonstrated experimentally, as exhibited inthe examples which follow, that the use of metronidazole in the form ofparticles having a specific range of diameters presents a very goodappetency; this is because the animals accept receiving the treatmentwithout refusing when it is administered to them directly in the mouthand spontaneously take food supplemented with the oily suspension orconsume it completely, in comparison with a nonsupplemented food; thisgood acceptance is observed only when the metronidazole is suspended inan oily vehicle, in particular oil; indeed, the applicant company hasbeen able to observe, during tests which it carried out, that theacceptance of metronidazole in the same form in aqueous suspension isnot satisfactory.

Surprisingly and although this range covers quite high particlediameters, the applicant company has been able to confirm that thephysical stability of the oily metronidazole suspensions according tothe invention is excellent and in accordance with regulatoryrequirements.

Preferably, the metronidazole content is between 8% and 17% byweight/volume.

The synthesis of metronidazole has been known since the 1960s and iswidely described in the state of the art (“Synthesis and trichomonacidalaction of metronidazole and its 4-nitroisomer”, Pershin et al.,Meditsinskaya Promyshlennost (1964), 18(10), 12-16, GB 939 681, FR 1 379915 or U.S. Pat. No. 3,178,446); this active principle can also beordered from suppliers of active principles.

The oily vehicle which is usable according to the invention is a vehiclepredominantly comprising oil, that is to say an edible animal, vegetableor mineral oil; it can be solid or liquid at ambient temperature;however, preference is given to oils which are liquid from 15° C. Usemay be made, among vegetable oils, of soybean oil, coconut oil, palmoil, sunflower oil or their mixture; these oils can also be modified orderived, as in Miglyol® products (SASOL), which are esters derived fromfatty acid, which is found, for example, in palm oil or coconut oil,coupled with glycerol or propylene glycol; the oil of animal origin canbe chosen from fish oils or cod liver oil and the mineral oil can beparaffin oil. The oil which is particularly suitable for theimplementation of the present invention is Miglyol, in particularMiglyol 812N.

The oral veterinary pharmaceutical composition according to theinvention can additionally comprise:

-   -   between 0.1% and 5% by weight/volume of viscosifying agent        chosen, for example, from aluminum mono-, di- or tristearate,        hydrophilic colloidal silica (Aerosil 200) or hydrogenated        castor oil (Cutina HR or Thixcin R); and/or    -   between 0.1% and 5% by weight/volume of at least one        surface-active principle chosen, for example, from: stearic        acid, polysorbate 80 (Tween 80) or any other nonionic        surfactant.

The oral veterinary pharmaceutical composition according to theinvention can also comprise:

-   -   between 0.1% and 15% by weight/volume of a natural or artificial        flavoring, preferably between 1% and 5% by weight/volume for        natural flavoring and between 1% and 3% by weight/volume for        artificial favoring; mention may be made of chicken liver        powder, baker's yeast, sucralose, chicken flavoring, anchovy        flavoring, sponge cake flavoring, brewer's yeast, meat meals,        fish meals, powders formed from cheeses or milk derivatives, and        their mixture; this flavoring can optionally be mixed with a        taste enhancer, such as monosodium glutamate;    -   between 0.005% and 2% by weight/volume of at least one        antioxidant, preferably between 0.01% and 0.5% by weight/volume,        chosen from butylated hydroxyanisole (BHA), butylated        hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate,        α-tocopherol and their mixtures.

The composition according to the invention can additionally comprisefood dyes conventionally formulated according to the general knowledgeof a person skilled in the art.

According to another of its subject matters, the present inventionrelates to the use of the compositions in the treatment of inflammatorydiseases of the intestines of domestic animals.

In the context of the present invention, domestic animals or petscomprise dogs, cats, rodents (hamsters, mice, rats or ferrets, forexample) and horses; the compositions according to the invention areparticularly suitable for the treatment of diarrhea and giardiasis; theyare also particularly suitable for the treatment of inflammatorydiseases of the digestive tract, such as inflammatory bowel disease(IBD) in dogs or chronic inflammation of the intestines in cats. In thecontext of this type of treatment, the recommended doses are such thatthey represent a contribution of metronidazole of between 10 and 15mg/kg of body weight administered twice daily; this type of treatmentgenerally lasts for 3 to 10 consecutive days, in particular for 5consecutive days.

The present invention also relates to the use of the oily metronidazolesuspensions in the treatment of diarrhea, in particular diarrhea ofparasitic or viral origin, in particular giardiasis, in domesticanimals, in particular in dogs. For the treatment of pathologies of thistype, the recommended doses are such that they represent a contributionof metronidazole of the order 25 mg/kg of body weight administered twicedaily; generally administered for 3 to 10 consecutive days, inparticular for 5 consecutive days.

The compositions are of particular use in the treatment of younganimals; the term “young animal” is understood to mean an animal whichhas not reached adult age and size; this age varies according to theanimal breeds under consideration; in the context of the presentinvention, it will be considered that young animal denotes an animalwhich is not adult and which is not capable of reproducing; usually,animals of less than 8 months, preferably of less than 6 months, areconcerned.

Thus, depending on the animals to be treated and on the nature and theseverity of their disorder, the compositions according to the inventionmust provide a contribution of metronidazole of between 10 and 50 mg/kgof body weight, preferably between 20 and 30 mg/kg of body weight,administered twice daily.

The concentrations and the volumes of the compositions according to theinvention are adjusted according to the therapeutic requirements(disease) and the weight of the animal to be treated; for reasons ofconvenience of administration, preference will be given, however, tocompositions having a volume of between 0.5 and 10 ml, preferablybetween 1 and 6 ml, more preferably of less than 3 ml.

According to a specific embodiment, the compositions according to theinvention are packaged in a device which makes possible the dosing; inparticular in a bottle, for example, having a volume of between 10 and100 ml, with a measuring container which makes possible the dosing, suchas a ladle, a pipette or a graduated syringe; the syringe exhibits theadvantage of making possible the administration of the medicamentdirectly into the mouth of the animal.

The compositions according to the invention exhibit a marked advantagebecause of their ease of use: the liquid form makes possible easy andrapid dosing; they can subsequently be administered directly into themouth of the animal, for example using a pipette, deposited alone in thebowl of the animal or also added to the food intake of the animal.

The process for the preparation of the compositions according to theinvention can be adjusted according to the viscosifying agent used.

For example, the specific case of the aluminum monostearate/stearic acidmixture (or of the aluminum distearate/stearic acid mixture) requires aprocess employing a phase of heating under strong shearing and then aphase of cooling under very low stirring in order not to break the gel.According to a specific example which a person skilled in the art willknow how to adjust according to the ingredients used, the process canuse a rotor/stator and a jacketed vessel and can comprise the followingstages:

-   -   mixing, with stirring and heating, the oil (for example,        Miglyol) and the antioxidant (for example, BHT);    -   adding stearic acid when the temperature reaches approximately        50° C. (this temperature can vary according to the scale on        which the process is carried out);    -   adding aluminum mono-, di- or tristearate when the temperature        reaches approximately 90° C.;    -   maintaining strong shearing at approximately 120° C. for 20        minutes;    -   cooling under very low stifling;    -   adding the metronidazole at a stirring speed which is low but        which makes possible a good dispersion of the active principle;    -   adding the appetizing substance (for example, chicken liver        powder) at a stirring speed which is low but which makes        possible a good dispersion of the appetizing substance.

In the case where the chosen viscosifying agent would result in asuspension, such as, for example, a silica, the preparation processmight be carried out with a necessary rotor/stator and might comprisethe following stages:

-   -   mixing, with stifling and heating, the oil (for example,        Miglyol), the antioxidant (for example, BHT) and the surfactant;    -   adding the silica with stirring;    -   adding the metronidazole with stirring which makes possible a        good dispersion of the active principle;    -   adding the appetizing substance (for example, chicken liver        powder) with stifling which makes possible a good dispersion of        the appetizing substance.

Here again, this is a specific example which a person skilled in the artwill know how to adjust according to the geometry of the equipment andthe ingredients used.

EXAMPLES Example 1

The inventors first tested the acceptance of an oily metronidazolesuspension alone; the aim of this study is to assess the spontaneoustaking of metronidazole in the form of an oily suspension (liquid)presented alone in the bowls of animals.

The formulation tested has the following composition: 16.67% byweight/volume of metronidazole (with D50 at 67 μm and D90 at 154 μm,which means that 50% of the metronidazole particles have a diameter ofless than 67 μm and that 90% of the metronidazole particles have adiameter of less than 154 μm) in Miglyol 812N, with 2% by weight/volumeof aluminum monostearate or distearate, 4% by weight/volume of stearicacid, 5% by weight/volume of chicken liver powder and 0.02% byweight/volume of BHT, packaged in a brown glass bottle.

The tests on the taking of metronidazole were carried out on three dogsof the beagle breed having a mean weight of 10 kg; the metronidazole ispresented for one hour to the dogs once daily for 6 days.

On each day of treatment, each animal received 3 ml/10 kg (the volume ofproduct administered per animal remains the same throughout the durationof the study).

Out of the three animals tested, one tasted the suspension on the firsttwo days, sniffed it on the following two days and ignored it on thefinal two days; the two other dogs consumed everything.

Conclusion: the oily metronidazole suspension according to theinvention, administered to dogs for 6 consecutive days, presented alonein their bowls, was well appreciated by the majority of the animals.

Example 2

The aim of the study is to assess the taking of metronidazole in theliquid form over a defined amount of dry dog food.

The composition of each of the metronidazole suspensions tested isdescribed in detail in the tables below, which also show the particlesize characteristics of the metronidazole.

The tests on the taking of metronidazole were carried out on dogs of thebeagle breed; these dogs, having a mean weight of 10 kg, receive 30 g ofdry dog food to which the metronidazole suspension is added.

Various acceptance tests were carried out; each of these tests iscarried out on 6 dogs by depositing a dose of suspension representing acontribution of 500 mg of metronidazole over 30 g of dry dog food; thecompositions of the suspensions tested, the characteristics of themetronidazole used and the total consumption by the dogs are describedin detail in the tables below.

The term “total taken” is understood to mean the amount of activeprinciple taken by the dog (followed or not followed by swallowing) andthe term “total consumption” is understood to mean the feed intakeingested (swallowed) by the dog.

It should be emphasized that the evaluation of the acceptance of theproducts tested is carried out under strict conditions since it is basedon their total consumption.

Oily Suspensions Devoid of Appetizing Substance

The tests carried out with oily metronidazole suspensions at differentparticle sizes which do not comprise appetizing substance are summarizedin table I:

TABLE I Compositions of the oily suspensions tested Metronidazole 16.6716.67 16.67 16.67 USP/EUR Ph Particle size (sieved D50: 67 μm  D50: 72μm  D50: 98 μm  of the 90 μm) D90: 154 μm D90: 187 μm D90: 223 μmmetronidazole 90 μm particles max Miglyol 812N 77.31 82.33 82.33 77.31Aluminum 2.00 1.00 1.00 2.00 monostearate Stearic acid 4 4 BHT 0.02 0.02Total (%) 100.00 100.00 100.00 100.00 Results % of total 90 100 90 96.7taken % of total 53.3 73.3 73.3 60 consumption

The results of table I show a good acceptance of the suspension devoidof appetizing substance when it is added to dry dog food; however, it isobserved that the acceptance depends on the size of the metronidazoleparticles, the best results being obtained with a D90 of 154 μm and of187 μm.

Oily Suspensions with Appetizing Substance, with or without TasteEnhancer

Similar tests carried out with oily metronidazole suspensions comprisingan appetizing substance (chicken liver powder) are presented in tableII:

TABLE IIa Compositions of the oily suspensions tested Metronidazole16.67 16.67 USP/EUR Ph Particle size D50: 2.8 μm D50: 2.8 μm D90: 6 μm  D90: 6 μm   Miglyol 812N 76.33 77.33 Aluminum monostearate 1.00 1.00Stearic acid BHT Monosodium glutamate 1.00 Chicken liver powder 5.005.00 Total (%) 100.00 100.00 Results % of total taken 90 90 % of totalconsumption 40 43.3

TABLE IIb Metronidazole USP/EUR Ph 16.67 16.67 16.67 16.67 17.84 16.6716.67 Compositions of the oily Particle size (sieved (sieved (sieved(sieved (sieved (sieved (sieved suspensions tested on on on on on on on50 μm) 90 μm) 125 μm) 150 μm) 150 μm) 150 μm) 180 μm) Miglyol 812 N72.31 72.31 72.31 72.31 75.16 72.31 72.31 Aluminum 2.00 2.00 2.00 2.001.00 2.00 2.00 monostearate Stearic acid 4.00 4.00 4.00 4.00 4.00 4.00BHT 0.02 0.02 0.02 0.02 0.02 0.02 Monosodium 1.00 glutamate Chickenliver 5.00 5.00 5.00 5.00 5.00 5.00 5.00 powder Total (%) 100.00 100.00100.00 100.00 100.00 100.00 100.00 Results % of total 96.7 96.7 96.7 10096.7 96.7 90 taken % of total 56.7 56.7 50 60 83.3 60 56.7 consumption

Tables IIa and IIb show a good acceptance of the oily metronidazolesuspensions, with the proviso that the latter are prepared with aspecific particle size range of the metronidazole particles:

Oily Suspensions with Appetizing Substance at Different MetronidazoleContents

TABLE III Metronidazole USP/EUR Ph 16.67 12.5 10 8.33 Particle size D50:67 μm  D50: 67 μm  D50: 67 μm  D50: 67 μm  D90: 154 μm D90: 154 μm D90:154 μm D90: 154 μm Miglyol 812N 77.33 81.50 84.00 85.67 Aluminum 1.001.00 1.00 1.00 monostearate Chicken liver 5.00 5.00 5.00 5.00 powderTotal (%) 100.00 100.00 100.00 100.00 % of total taken 93.3 96.7 10096.7 % of total 80 80 90 93.3 consumption

These results show that the metronidazole content has an influence onthe total consumption of the suspension; however, this consumptionremains highly satisfactory under the conditions tested.

These combined tests carried out confirm the excellent acceptance of theoily metronidazole suspensions according to the invention.

1.-15. (canceled)
 16. An oral veterinary pharmaceutical compositionconsisting of an oily metronidazole suspension comprising: a) between 5%and 30% by weight/volume of metronidazole; and b) between 70% and 95% byweight/volume of at least one edible animal, vegetable or mineral oil;wherein the metronidazole is provided in the form of particles, 90% ofwhich have an equivalent diameter strictly of greater than 6 μm and lessthan or equal to 300 μm.
 17. The oral veterinary pharmaceuticalcomposition of claim 16, wherein 90% of the metronidazole particles havean equivalent diameter of strictly between 50 and 250 μm.
 18. The oralveterinary pharmaceutical composition of claim 16, wherein 90% of themetronidazole particles have an equivalent diameter of strictly between90 and 200 μm.
 19. The oral veterinary pharmaceutical composition ofclaim 16, wherein 90% of the metronidazole particles have an equivalentdiameter of strictly between 125 and 200 μm.
 20. The oral veterinarypharmaceutical composition of claim 16, wherein the equivalent diameterof the metronidazole particles is measured by laser particle sizing. 21.The oral veterinary pharmaceutical composition of claim 16, wherein theoil is chosen from soybean oil, coconut oil, palm oil, Miglyol®, codliver oil, paraffin oil or their mixture.
 22. The oral veterinarypharmaceutical composition of claim 16, further comprising: a) between0.1% and 5% by weight/volume of a viscosifying agent chosen fromaluminum mono-, di- or tristearate, hydrophilic colloidal silica(Aerosil 200) or hydrogenated castor oil; and/or b) between 0.1% and 5%by weight/volume of at least one nonionic surface-active principle. 23.The oral veterinary pharmaceutical composition of claim 16, furthercomprising between 0.1% and 15% by weight/volume of a natural orartificial flavoring.
 24. The oral veterinary pharmaceutical compositionof claim 16, further comprising between 0.005% and 2% by weight/volumeof at least one antioxidant chosen from butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), propyl gallate, ascorbyl palmitate,α-tocopherol or their mixture.
 25. The oral veterinary pharmaceuticalcomposition of claim 24, wherein the at least one antioxidant is between0.1% and 0.5% by weight/volume.
 26. The oral veterinary pharmaceuticalcomposition of claim 16, wherein it is packaged in a device which makespossible the dosing thereof.
 27. A method for treating inflammatorydiseases of the intestines of domestic animals, the method comprisingadministering an effective amount of the oral veterinary pharmaceuticalcomposition of claim 16 to the domestic animal.
 28. A method fortreating diarrhea in domestic animals, the method comprisingadministering an effective amount of the oral veterinary pharmaceuticalcomposition of claim 16 to the domestic animal.
 29. The method of claim28, wherein the diarrhea is of parasitic or bacterial origin.
 30. Themethod of claim 29, wherein the diarrhea of parasitic origin isgiardiasis.
 31. The method of claim 28, wherein the domestic animal isyoung.
 32. The method of claim 31, wherein the domestic animal is a dogor a cat.
 33. The method of claim 27, wherein the oral veterinarypharmaceutical composition is administered at a dose representing acontribution of metronidazole of between 10 and 50 mg/kg of body weighttwice daily.
 34. The method of claim 27, wherein the oral veterinarypharmaceutical composition is administered for 3 to 10 consecutive days.35. The method of claim 34, wherein the oral veterinary pharmaceuticalcomposition is administered for 5 consecutive days.
 36. The method ofclaim 28, wherein the oral veterinary pharmaceutical composition isadministered at a dose representing a contribution of metronidazole ofbetween 10 and 50 mg/kg of body weight twice daily.
 37. The method ofclaim 28, wherein the oral veterinary pharmaceutical composition isadministered for 3 to 10 consecutive days.
 38. The method of claim 37,wherein the oral veterinary pharmaceutical composition is administeredfor 5 consecutive days.